The principal long-term goal of this work is to determine the genetic factors which control human immune responsiveness. Since the dosages of most inhaled allergens are immunogenically limiting, allergy provides a particularly good model for this study. We hypothesize that two principal immunogenetic factors control allergic response: HLA-linked loci which control specific antibody responses and non-HLA-linked loci which regulate overall IgE responsiveness. To study HLA-linked control of immune response, our approach will be to define associations between specific HLA types and responsiveness to various well-defined ultrapure allergens in populations, followed by HLA linkage studies in families. Both the family and population studies will include the use of allergen immunotherapy with defined antigen doses. The molecular basis of the associations will be defined in terms of HLA-D region gene sequences. To investigate the regulation of total IgE level, which is controlled by non-HLA-linked genes, our approach includes genetic-epidemiologic studies and investigation of the role of glycosylation-inhibiting factor (GIF/lipocortin) and glycosylation- enhancing factor (GEF). The prototype antigens for the specific immune response studies are three species of ragweed Amb V homologues, where there is a striking relationship between immune responsiveness and HLA- DR2/Dw2 in all cases. We will investigate the structural basis for immune recognition of three Amb V homologues by sequencing HLA-D-region genes of five different groups of subjects, who have different immune response phenotypes to the Amb V molecules, but the same HLA-DR specificity, namely DR2. "Immune response clusters" toward 35 different allergenic extracts, and their relationship with HLA type, will also be studied. We will continue genetic analyses of factors regulating total serum IgE level, an important step in determining the genetics of allergic disease. Further studies will include: 1) computer simulation of family data to investigate whether current analytical methods are powerful enough to detect the presence of an IgE-regulating gene; 2) investigation of possible genetic heterogeneity in families to determine whether there is a subset of families with a major gene for IgE level; 3) studies of the genetics of GIF and GEF levels to determine their effect on IgE regulation.